Manganese (Mn) toxicity is characterized by a collection of neurological symptoms similar to the extrapyramidal dysfunction associated with Parkinson's disease. In the US and other developed countries, manganism is primarily an occupational disorder most often seen in the welding profession because welding rods contain relatively high quantities of Mn. Gases that are given off by the extreme heat generated from the welding guns vaporize the Mn in the rods which is either taken up into the lungs and subsequently transported into the circulation or directly transported into the CNS via retrograde transport through the olfactory neurons impinging on the nasal cavity. Epidemiological studies and case reports indicate that prolonged exposure to high atmospheric levels of Mn can cause hearing impairment. In support of these clinical reports is a recently published study from our laboratory demonstrating for the first time that M levels of Mn initially damages spiral ganglion neurons and then the sensory hair cells in organotypic cultures of rat inner ear. Preliminary in vivo studies indicate that Mn can impair hearing and damage cochlear neurons in rats. This is consistent with another recent report, demonstrating that welding fumes induce hearing impairment in rabbits and that the hearing deficits are exacerbated by exposure to noise. Since Mn has been reported to accumulate in the inner ear (cochlea) following acute treatment, we hypothesize that it has the potential to damage the sensory hair cells that convert sound into neural activity or spiral ganglion neurons (SGN) that transmit acoustic information from the hair cells to the brain via the auditory nerve. Moreover, we hypothesize that Mn-induced hearing loss observed in welders is exacerbated by the high levels of noise present in the occupational working environment. To test these hypotheses, we propose perform in vivo studies to establish a dose-time response relationship for the ototoxic effects of Mn administered orally to rats. We will test the hypothesis that concurrent exposure to high level of continuous noise will exacerbate hearing impairment and cochlear pathology induced by Mn. We will also correlate the extent of hearing impairment with Mn concentrations in the inner ear as a function of time and dose and noise exposure. To accomplish this, we will determine the degree of hearing impairment that develops from various doses of Mn alone, noise alone and Mn plus noise. We will also compare and evaluate histopathological damage produced by Mn, noise and the combination of Mn plus noise; this will be accomplished by assessing degeneration of the stria vascularis, hair cells and SGN death. We will correlate the degree of hearing impairment and cochlear histopathologies for each treatment paradigm with the Mn concentration in the cochlea. PUBLIC HEALTH RELEVANCE: Several reports in the literature have described hearing deficits both in welders who are normally exposed to chronic high levels of Mn and in individuals exposed simultaneous to noise and Mn. Our recent published findings demonstrate that exposure to Mn can cause degeneration of cells within the inner ear and further reveal that these lesions can provoke auditory impairment in rats treated with the divalent metal. The relevance of the studies proposed will enable us to understand the mechanism for Mn-induced auditory loss with the intent to find new treatments to prevent this from occurring.